The goals of this proposal are to improve our understanding of both the evolution and management of influenza by developing a unified modeling framework. In particular, the questions we will address are (1) How do given strain and subtype structures, and the associated patterns of cross-reactivity, affect disease dynamics? (2) How does cross-reactivity affect pathogen evolution? (3) How do strain structure and patterns of cross-reactivity self-organize over evolutionary time, for example into quasi-species, and how does this organization feed back to affect dynamics? (4) What are the implications of these issues for vaccination strategies, and what are the reciprocal effects of vaccination programs upon the organization of the viral population?